Zika virus spreads through infection of lymph node-resident macrophages

Reynoso, Glennys V.; Gordon, David; Kalia, Anurag; Aguilar, Cynthia C.; Malo, Courtney S.; Aleshnick, Maya; Dowd, Kimberly A.; Cherry, Christian R.; Shannon, James A.; Vrba, Sophia M.; Holmes, Autumn C.; Alippe, Yael; Maciejewski, Sonia; Asano, Kenichi; Diamond, Michael S.; Pierson, Theodore C.; Hickman, Heather D.

doi:10.1016/j.celrep.2023.112126

Cited by 18 publications

(21 citation statements)

References 72 publications

(88 reference statements)

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“…We next examined ZIKV transit through these draining LNs. We have previously shown that the popliteal LN can capture at least 1 × 10 4 focus-forming units (FFU) of FP-inoculated ZIKV, preventing iliac LN infection by the initial viral inoculum ( 14 ). In these experiments, inoculation of Ifnar1 −/− mice [used due to the inability of ZIKV H/PF/2013 to antagonize murine type I interferon (IFN-I) responses and efficiently replicate in wild-type adult mice ( 27 )] resulted in viremia that peaked on day 3 and waned by day 5 postinfection (pi).…”

Section: Resultsmentioning

confidence: 99%

“…Macrophages in LN sinuses (SSMs and MSMs) undergo attrition after viral infection ( 14 , 21 , 22 , 31 ). We have previously shown that ZIKV inoculation of the hind FP induces marked SSM attrition in the draining LN within 24 hours ( 14 ). Thus, SSM death serves a sensitive indicator of LN infection.…”

Section: Resultsmentioning

confidence: 99%

“…After subcutaneous virus inoculation, virus transits quickly to the LN via the lymphatics. Lymph-borne virus first arrives in the SCS and can be captured by SSMs, even in the absence of virus-specific antibody (Ab), complement, or viral protein glycosylation (1,4,(11)(12)(13)(14)(15)(16)(17)(18). Because Ag must be labeled for imaging approaches, it has been experimentally challenging to track viral Ag movement after the initial inoculum of labeled viral particles or proteins.…”

Section: Introductionmentioning

confidence: 99%

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Subcapsular sinus macrophages maximize germinal center development in non-draining lymph nodes during blood-borne viral infection

Aguilar,

Kalia,

Brisse

et al. 2024

Sci. Immunol.

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Lymph node (LN) germinal centers (GCs) are critical sites for B cell activation and differentiation. GCs develop after specialized CD169 + macrophages residing in LN sinuses filter antigens (Ags) from the lymph and relay these Ags into proximal B cell follicles. Many viruses, however, first reach LNs through the blood during viremia (virus in the blood), rather than through lymph drainage from infected tissue. How LNs capture viral Ag from the blood to allow GC development is not known. Here, we followed Zika virus (ZIKV) dissemination in mice and subsequent GC formation in both infected tissue–draining and non-draining LNs. From the footpad, ZIKV initially disseminated through two LN chains, infecting LN macrophages and leading to GC formation. Despite rapid ZIKV viremia, non-draining LNs were not infected for several days. Non-draining LN infection correlated with virus-induced vascular leakage and neutralization of permeability reduced LN macrophage attrition. Depletion of non-draining LN macrophages significantly decreased GC B cells in these nodes. Thus, although LNs inefficiently captured viral Ag directly from the blood, GC formation in non-draining LNs proceeded similarly to draining LNs through LN sinus CD169 + macrophages. Together, our findings reveal a conserved pathway allowing LN macrophages to activate antiviral B cells in LNs distal from infected tissue after blood-borne viral infection.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Subcapsular sinus macrophages maximize germinal center development in non-draining lymph nodes during blood-borne viral infection

Aguilar,

Kalia,

Brisse

et al. 2024

Sci. Immunol.

Self Cite

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“…Indeed, signs of active viral infection in LNSCs are unique and have rarely been identified. Instead, much research has focused on LN resident macrophages, which interact with and can be targeted by viruses such as Zika virus, vaccinia virus, and vesicular stomatitis virus (77)(78)(79). However, lymphocytic choriomeningitis virus (LCMV) has been shown to target murine FRCs within lymphoid organs, and importantly, LCMV infection of FRCs was significantly higher for the chronic strain clone 13, which establishes a persistent infection, than the acute strain Armstrong, which is cleared efficiently by CD8 + T cells (80).…”

Section: Discussionmentioning

confidence: 99%

Chikungunya virus infection disrupts lymph node lymphatic endothelial cell composition and function via MARCO

Lucas,

Sheridan,

Reynoso

et al. 2023

Preprint

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Infection with chikungunya virus (CHIKV) causes disruption of draining lymph node (dLN) organization, including paracortical relocalization of B cells, loss of the B cell-T cell border, and lymphocyte depletion that is associated with infiltration of the LN with inflammatory myeloid cells. Here, we find that during the first 24 h of infection, CHIKV RNA accumulates in MARCO-expressing lymphatic endothelial cells (LECs) in both the floor and medullary LN sinuses. The accumulation of viral RNA in the LN was associated with a switch to an antiviral and inflammatory gene expression program across LN stromal cells, and this inflammatory response, including recruitment of myeloid cells to the LN, was accelerated by CHIKV-MARCO interactions. As CHIKV infection progressed, both floor and medullary LECs diminished in number, suggesting further functional impairment of the LN by infection. Consistent with this idea, we find that antigen acquisition by LECs, a key function of LN LECs during infection and immunization, was reduced during pathogenic CHIKV infection.

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“…Optimal adaptive immune responses to pathogens depend on presentation of pathogen-derived antigens in the LN, a process mediated by afferent lymphatic vessels 21 . Afferent lymphatic vessels transport lymph containing antigens, antigen presenting cells, and in some cases viable pathogens into the subcapsular sinus of the LN [34][35][36] . Pathogen dissemination to the LN, however, has the potential to impair ongoing or future adaptive immune responses 37 .…”

Section: Discussionmentioning

confidence: 99%

Lymphatic vessel transit seeds precursors to cytotoxic resident memory T cells in skin draining lymph nodes

Heim,

Schultz,

Delclaux

et al. 2023

Preprint

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Resident memory T cells (TRM) provide rapid, localized protection in peripheral tissues to pathogens and cancer. While TRM are also found in lymph nodes (LN), how they develop during primary infection and their functional significance remains largely unknown. Here, we track the anatomical distribution of anti-viral CD8+ T cells as they simultaneously seed skin and LN TRM using a model of skin infection with restricted antigen distribution. We find exquisite localization of LN TRM to the draining LN of infected skin. LN TRM formation depends on lymphatic transport and specifically egress of effector CD8+ T cells that appear poised for residence as early as 12 days post infection. Effector CD8+ T cell transit through skin is necessary and sufficient to populate LN TRM in draining LNs, a process reinforced by antigen encounter in skin. Importantly, we demonstrate that LN TRM are sufficient to provide protection against pathogenic rechallenge. These data support a model whereby a subset of tissue infiltrating CD8+ T cells egress during viral clearance, and establish regional protection in the draining lymphatic basin as a mechanism to prevent pathogen spread.

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Zika virus spreads through infection of lymph node-resident macrophages

Cited by 18 publications

References 72 publications

Subcapsular sinus macrophages maximize germinal center development in non-draining lymph nodes during blood-borne viral infection

Subcapsular sinus macrophages maximize germinal center development in non-draining lymph nodes during blood-borne viral infection

Chikungunya virus infection disrupts lymph node lymphatic endothelial cell composition and function via MARCO

Lymphatic vessel transit seeds precursors to cytotoxic resident memory T cells in skin draining lymph nodes

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